Atherosclerosis is a degenerative disease of medium- and large-sized arteries. It is the major cause of acute myocardial infarction, stroke and peripheral artery disease. The first stages of the disease are characterized by accumulation of cholesterol-loaded macrophages forming small fatty streaks on the inside of the arterial wall. Activation of a chronic inflammatory process within these fatty streaks leads to the formation of raised fibromuscular plaques with various degree of extracellular lipid and cell necrosis. In plaques with extensive cell death and inflammation the fibrous cap covering the core of lipid deposits becomes eroded increasing the risk for plaque rupture and thrombotic occlusion of the vessel, i.e. the major cause of acute clinical events.
The disease is initiated by accumulation of lipoproteins, primarily LDL, in the extracellular matrix of the arterial intima. This accumulation is caused by binding of positively charged amino acids in the LDL protein apo B-100 to negatively charged matrix glycoproteins. The entrapped LDL aggregates and becomes oxidized in response various enzymes and oxygen radicals present in the arterial wall. The oxidation of LDL is associated with formation of a number of highly reactive compounds such as aldehydes, lipid peroxides and oxysterols that will cause neighbouring endothelial cells to express adhesion molecules and activate an inflammatory response. As a result monocytes and T cells will infiltrate the affected intima and the monocytes will differentiate into macrophages expressing different types of scavenger receptors. These receptors effectively bind and mediate the uptake and removal of oxidized LDL from the extracellular matrix. The macrophages will subsequently express oxidized LDL antigens associated with HLA-DR receptors. Recognition of these antigens by specific T cells results in activation of an adaptive immune response against oxidized LDL. The important role of this immune response in the development of atherosclerosis is becoming increasingly recognized.
The oxidation of LDL is also associated with a degradation of apo B-100 into peptide fragments that are further modified by reaction aldehydes such as malondialdehyde (MDA) and 4-hydroxynonenal. These aldehyde-modified peptide fragments become major targets for the immune system and antibodies against MDA-modified apo B-100 fragments are frequently encountered in human plasma. The role of these immune responses remains to be fully characterized but animal experiments demonstrating that immunization with oxidized LDL inhibits the development of atherosclerosis suggest that at least some of these immune responses have a protective effect.